Oxidative stress mechanisms regulating gamma-globin gene transcription in sickle cell disease

镰状细胞病中调节伽马珠蛋白基因转录的氧化应激机制

基本信息

批准号：
10340421
负责人：
Rahima Zennadi
金额：
$ 61.02万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-07-01 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10340421
关键词：
Address Advanced Development Affect Anemia Automobile Driving Bone Marrow Cessation of life Chemicals Chronic Chronic stress Clinical DNA DNA Methylation DNA Modification Process Data Development Dioxygenases Electronic Medical Records and Genomics Network Enzymes Epigenetic Process Erythroblasts Erythrocytes Erythroid Erythropoiesis Event Extramedullary Hematopoiesis FOXO3A gene Fetal Hemoglobin Foundations Functional disorder Gene Expression Gene Expression Regulation Gene Silencing Genes Genetic Transcription Globin Goals Hemolysis Hereditary Disease Histone Acetylation Histone Deacetylase Hypoxia In Vitro Inherited Intervention Knock-out Knowledge MAPK3 gene Mediating Mediator of activation protein Mendelian disorder Messenger RNA Morbidity - disease rate Mus Names Organ Oxidative Stress Pain Pathogenesis Pathway interactions Patients Point Mutation Production Protein translocation Reactive Oxygen Species Regulation Regulator Genes Role Severities Sickle Cell Sickle Cell Anemia Sickle Hemoglobin Splenomegaly Stress Survival Rate Switch Genes Symptoms Untranslated RNA Vascular Diseases beta Globin biological adaptation to stress disease phenotype effective therapy epigenetic regulation fetal reactivity fetus cell gamma Globin gene induction gene repression hematopoietic tissue histone modification improved in vivo insight mouse model novel oxidative damage premature prevent progenitor reduce symptoms sickle erythroid sickling therapeutic target transcription factor vaso-occlusive crisis

项目摘要

Oxidative stress mechanisms regulating g-globin gene transcription in sickle cell disease Abstract: Sickle cell disease (SCD) is the most common inherited monogenic disorder affecting the β-globin gene, leading to the production of sickled-shaped red blood cells (RBCs). Patients with SCD suffer from severe anemia and painful vasoocclusive crises, which are both exacerbated by increased oxidative stress. Induction of normal, but developmentally silenced γ-globin gene of fetal hemoglobin (HbF) expression reduces RBC sickling-mediated vasoocclusion, and anemia, consequently ameliorating clinical severity of SCD. Reducing oxidative stress also improves SCD phenotypic severity. Yet effective treatment options remain limited. Understanding the pathogenesis of the erythroid mechanisms regulating oxidative stress and factors engaged in silencing γ-globin gene, is of substantial value to SCD patients. Our data uncovered an unanticipated role for mediators of oxidative stress in RBC sickling, and in regulating the transcriptional regulatory machinery that represses γ-globin genes as well as epigenetic enzyme components associated with γ-globin to β-globin gene switch in erythroid progenitors. Here, to extend our studies, we will in vitro and in vivo genetically and/or chemically manipulate these mediators of oxidative stress and the regulated pathways using a SCD mouse model, and determine their effects on γ-globin gene regulation, and thus sickling, and their mechanism of action on the transcriptional regulatory machinery that silences γ-globin gene during sickle RBC production. We will also determine the contribution of these mediators in epigenetic DNA and histone modifications associated with γ-globin to β-globin gene switch during sickle RBC production. Because stress erythropoiesis compensates for anemia caused by oxidative damage to the RBCs, we will further validate the effects of these mediators of oxidative stress on stress erythropoiesis in splenic hematopoietic tissue and examine their role in chronic erythroid stress-response, specifically in erythroid terminal maturation and enucleation. We strongly believe that our studies will provide novel and unprecedented insights into the exact mechanisms regulating γ-globin gene silencing and γ-globin to β-globin gene switch in SCD, as well as ineffective erythroid maturation and enucleation. Our long- term goal is to identify remediable sickle erythroid abnormalities to improve SCD pathophysiology. In addition, our studies will lay the foundation for more rational approaches to therapies that better alleviate SCD clinical symptoms.

镰状细胞病中调节 g 珠蛋白基因转录的氧化应激机制抽象的：镰状细胞病 (SCD) 是影响 β-珠蛋白的最常见的遗传性单基因疾病基因，导致镰状红细胞 (RBC) 的产生，患有 SCD 的患者会遭受这种痛苦。严重贫血和痛苦的血管闭塞危机，这些都会因氧化增加而加剧诱导正常但发育沉默的胎儿血红蛋白 (HbF) γ-珠蛋白基因。表达减少红细胞镰状细胞介导的血管闭塞和贫血，从而改善减少氧化应激也可改善 SCD 表型的严重程度。了解红细胞增多症的发病机制仍然有限。调节氧化应激的机制和参与沉默 γ-珠蛋白基因的因素，具有重要意义我们的数据揭示了氧化应激介质在 SCD 患者中的意想不到的作用。红细胞镰状细胞，以及调节抑制 γ-珠蛋白基因的转录调控机制以及与红系中 γ-珠蛋白到 β-珠蛋白基因转换相关的表观遗传酶成分在这里，为了扩展我们的研究，我们将在体外和体内进行遗传和/或化学研究。使用 SCD 小鼠模型操纵这些氧化应激介质和调节途径，并确定它们对 γ-珠蛋白基因调控以及镰状化的影响，以及它们的机制镰状红细胞过程中对沉默 γ-珠蛋白基因的转录调节机制的作用我们还将确定这些介质在表观遗传 DNA 和组蛋白中的贡献。与 γ-珠蛋白相关的修饰镰状红细胞生产过程中β-珠蛋白基因转换。应激性红细胞生成可补偿红细胞氧化损伤引起的贫血，我们将进一步验证这些氧化应激介质对脾脏应激性红细胞生成的影响造血组织并检查它们在慢性红细胞应激反应中的作用，特别是在我们坚信我们的研究将提供新颖的红细胞末端成熟和去核。以及对调节 γ-珠蛋白基因沉默和 γ-珠蛋白的确切机制的前所未有的见解 SCD 中的 β-珠蛋白基因转换，以及无效的红系成熟和去核。长期目标是确定可治愈的镰状红细胞异常，以改善 SCD 的病理生理学。此外，我们的研究将为更合理的治疗方法奠定基础， SCD 缓解临床症状。